Original Article / Orijinal Makale Endocrinology / Endokrinoloji
Monocyte to HDL Cholesterol Ratio and its association with cardio-metabolic risk factors in Primary Hyperparathyroidism
Primer Hiperparatiroidili hastalarda monosit sayısının HDL Kolesterole oranı ve bu oranın kardiyo-metabolik risk faktörleri ile ilişkisi
Muhammed KIZILGÜL1, Mustafa ÇALIŞKAN1, Bekir UÇAN1, Selvihan BEYSEL1, Mümtaz TAKIR2, Erkam SENCAR1, Davut SAKIZ1, Erman ÇAKAL1, Mustafa ÖZBEK1
Received: 16.03.2018 Accepted: 13.04.2018
1Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey
2Department of Endocrinology and Metabolism, Medeniyet University, Goztepe Training and Research Hospital, Istanbul, Turkey
Yazışma adresi: Muhammed Kızılgül, Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey
e-mail: muhammedkzgl@gmail.com
INTRODUCTION
Primary hyperparathyroidism (PHPT) is described
as elevated levels of serum calcium and parathyroid hormone (PTH)
1. The incidence of PHPT is increasing substantially in countries that laboratory screening
ABSTRACT
The monocyte count to HDL-Cholesterol ratio (MHR) has been shown as a novel prognostic indicator of cardiovascular disea- ses. Several studies demonstrated that even mild primary hyper- parathyroidism (PHPT) has an increased risk for cardiovascular disease. We aimed to evaluate MHR and its relation with cardio- metabolic risk factors in patients with PHPT. Seventy-five pa- tients with PHPT and 96 control subjects were included in the study. Demographic, anthropometric, and biochemistry results were recorded. The groups were compared in terms of monocy- te counts, HDL-cholesterol (HDL-C), and MHR values. Correlati- on analysis was used to determine the relation between MHR and cardio-metabolic parameters. The mean age was similar in each group (52.69±10.91 to 53.33±7.70 years, p=0.667). Sex distribution and body mass index were similar in each group (p>0.05). Monocyte counts and HDL-C levels were similar in each group (479.73±136.97 vs 500.13±144.06 and 51.54±11.99 vs 51.95±11.66 mg/dL, p>0.05). MHR was similar between groups (9.71±3.65 vs 10.11±3.86, p>0.05). MHR was positively correla- ted with systolic blood pressure (SBP) and homeostasis model assessment of insulin resistance (HOMA-IR) (r2=0.276, p=0.019 and r2=0.271, p=0.020, respectively). There was no association between MHR and other cardio-metabolic risk factors including diastolic blood pressure (DBP), carotid intima media thickness (CIMT), and c-reactive protein (CRP) (p>0.05). The MHR did not increase in patients with PHPT. The MHR was correlated with SBP and HOMA-IR; however, it was not associated with other cardio- metabolic risk factors including DBP, CIMT, and CRP.
Keywords: Primary hyperparathyroidism, cardio-metabolic risk factors, monocyte count to HDL-C ratio
ÖZ
Monosit sayısının HDL-Kolesterole oranı (MHO)’nın yeni bir kar- diyovasküler belirteç olduğu gösterilmiştir. Çoğu çalışmada, hafif primer hiperparatiroidi (PHPT)’nin bile kardiyovasküler hasta- lık riskini arttırdığı bildirilmiştir. Bu çalışmada, MHO’nun PHPT hastalarında yüksek olup olmadığını ve kardiyo-metabolik risk faktörleri ile ilişkisini değerlendirmeyi amaçladık. Çalışmaya pri- mer hiperparatiroidisi olan 75 hasta ve 96 kontrol olgusu alındı.
Demografik, antropometrik ve biyokimyasal veriler kaydedildi.
Gruplar, monosit sayıları, HDL-Kolesterol (HDL-K) ve MHO’na göre karşılaştırıldı. MHO ile laboratuvar ve kardiyo-metabolik risk faktörleri arasındaki ilişki korrelasyon analizi ile değerlen- dirildi. Ortalama yaş her iki grupta benzerdi (52,69±10,91’e karşın 53,33±7,70, p:0,667). Cinsiyet dağılımı, vücut kitle in- deksi (VKİ) gruplar arası benzerdi (p>0,05). Monosit sayısı ve HDL-K düzeyleri gruplar arası benzerdi (479,73±136,97’ye karşın 500,13±144,06’ya karşın, 51,54±11,99 to 51,95±11,66, p>0,05).
MHO gruplar arası benzerdi (9,71±3,65’e karşın, 10,11±3,86, p>0,05). MHO sistolik kan basıncı ve insulin direnci (HOMA-IR) ile pozitif korrele idi (r2:0,276, p:0,019 ve r2:0,271, p:0,020). MHO ile diğer kardiyovasküler risk faktörleri olan diastolik kan basıncı, karotis intima media kalınlığı (KIMK) ve c-reaktif protein (CRP) arasında korrelasyon saptanmadı (p>0,05). Monosit sayısının HDL-Kolesterole oranı primer hiperparatiroidili hastalarda yük- sek değildi. Monosit sayısının HDL-Kolesterole oranı sistolik kan basıncı ve insülin direnci ile korrele iken, diğer kardiyovasküler risk faktörleri olan diastolik kan basıncı, KIMK ve CRP ile korrele değildi.
Anahtar kelimeler: Primer hiperparatiroidi, monosit sayısının HDL-Kolesterole oranı, kardiyo-metabolik risk faktörleri
tests have come into use
2.
Monocytes, as a source of several cytokines, directly affect platelets and endothelial cells, which induces proinflammatory and prothrombotic pathways
3. Mo- nocytes accumulate in lipids and differentiate into macrophages, which release metalloproteinases including elastase and collagenase, thereby causing atherosclerosis
4. However, high-density lipoprote- in cholesterol (HDL-C) interferes with the effects of monocytes, which decreases the risk of cardiovascu- lar diseases (CVD)
5,6. There is increasing interest in describing novel prognostic markers to facilitate the categorization of patients who have a greater risk for CVD. The monocyte count to HDL-C ratio (MHR) was postulated as a novel marker of prognosis for the de- velopment of future CVD
7,8. A growing body of evi- dence supports that even mild PHPT has an elevated risk for CVD
9-13.
We investigated the MHR and its relation to cardio- metabolic risk factors in patients with PHPT.
MATERIAL and METHOD Patient selection
Seventy-five patients who were diagnosed as ha- ving PHPT at Diskapi Training and Research Hospital between 2012 and 2016 and 96 controls were inc- luded in the study. Local ethics committee approval (06.11.2017-42/14) from Diskapi Training and Rese- arch Hospital was obtained and all participants provi- ded written informed consent before the study began.
Patients with multiple endocrine neoplasias, parath- yroid cancer, thyroid cancer, hyperparathyroidism- jaw tumor syndrome, and patients on drugs that counteract with calcium and vitamin D metabolism were excluded from the study. Diagnosis PHPT was defied as persistent hypercalcemia with normal or non-suppressed PTH concentrations
14.
Clinical, biochemical and hormonal measurements Basal demographic data, clinical features, carotid
intima media thickness (CIMT) measurements were recorded for all participants. Weight, height, circum- ferences of waist (WC), body mass index (BMI), and systolic and diastolic blood pressure (SDP and DBP, respectively) were measured. Fasting state bioche- mical and hormonal measurements were perfor- med in the morning using colorimetric methods and complete blood counts were obtained from all par- ticipants. An intact chemiluminescent immunoassay of PTH (Immulite 2000) was used to measure serum PTH levels. 25-OH vitamin D concentrations were measured using a radioimmune assay.
High-resolution B-mode ultrasound (EUB 7000 HV;
Hitachi, Tokyo, Japan) with a 13-MHz linear array transducer was used to image parathyroids. Carotid intima-media thickness (CIMT) was measured to as- sess carotid atherosclerosis. In healthy middle-aged individuals, CIMT between 0.6 and 0.7 mm is accep- ted as normal, however, CIMT of ≥1 mm is associated with higher risk for CVD
15. CIMT was measured by a B-mode imaging high-resolution ultrasound (EUB 7000 HV; Hitachi, Tokyo, Japan). CIMT was descri- bed as the distance between the blood-intima and media-adventitia boundaries on B-mode imaging high-resolution ultrasound system. All ultrasonog- raphic measurements were performed by the same investigator (MC).
Statistical analysis
All statistical analyses were performed by using the JMP 13.0.1 software (SAS Institute, Cary, NC, USA).
Quantitative data are expressed as mean ± standard
deviation, or counts and proportions for categori-
cal data. Normality of distribution was examined by
using the Kolmogorov-Smirnov or Shapiro-Wilk W
test. The chi-square or Fisher’s exact test was used
when variables are categorical. Student’s t-test was
used for normally distributed continuous variables
and the Mann-Whitney U test for those that did not
fit normal distribution. Correlations were assessed
using Pearson’s and Spearman’s correlation. A p va-
lue lower than 0.05 was accepted statistically signi-
ficant.
RESULTS
Seventy-five patients with PHPT and 96 controls were enrolled in the study. The mean age was simi- lar in both groups (52.69±10.91 vs 53.33±7.70 ye- ars, p=0.667). Sex distribution and BMI was similar in each group (p=0.081 and p=0.159, respectively).
White blood cell count, vitamin D, fasting plasma glucose, creatinine, HDL-C, LDL-C, triglyceride and C-reactive protein (CRP) levels were similar between the groups. SBP and DBP, calcium, and parathormo- ne levels were higher in the PHPT group (p<0.0001).
Phosphorous levels were significantly lower in the PHPT group (p<0.0001). CIMT and HOMA-IR were increased in the PHPT group (p<0.05). Monocyte counts and HDL-C levels were similar in both gro- ups (479.73±136.97 vs 500.13±144.06, p=0.374 and 51.54±11.99 vs 51.95±11.66, p=0.825) (Table 1).
The MHR was similar in both groups (9.71±3.65 vs 10.11±3.86, p=0.506). MHR and SBP and HOMA-IR were positively correlated (r
2=0.276, p=0.019 and r
2=0.271, p=0.020). The MHR was not related to ot-
her cardio-metabolic risk factors including DBP, CIMT and CRP (Table 2).
DISCUSSION
Our aim was to evaluate the correlation between
Table 1. Clinical and demographic characteristics of patients and controls.
Age (years) Sex (Female) BMI (kg/m2)
Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) White blood cell count (x109/μL) Monocyte (x109/μl)
Monocyte/HDL ratio Calcium (mg/dl) Phosphorous (mg/dl) Parathormone (pg/mL) Vitamin D (ng/mL)
Fasting Plasma Glucose (mg/dL) Creatinine (mg/dl)
HDL-Cholesterol (mg/dL) LDL-Cholesterol (mg/dL) Triglyceride (mg/dL) CIMT (cm)
CRP (mg/L) HOMA-IR
Mean or n 52.69 65 30.61 136.56 83.81 6812.80 479.73 9.71 11.11 2.68 236.89 14.76 90.59 0.76 51.54 123.93 147.18 0.67 3.41 2.93
SD or % 10.91 87 5.12 15.10 7.46 1774.60 136.97 3.65 0.81 0.43 223.96 12.71 8.79 0.20 11.99 32.18 61.83 0.13 3.31 1.87
Abbreviations: BMI=body mass index; CIMT=carotid intima-media thickness; CRP=C-reactive protein; HOMA-IR=homeostasis model as- sessment of insulin resistance; SD=standard deviation
Mean or n 53.33 73 29.55 121.72 78.76 7169.21 500.13 10.11 9.37 3.44 60.55 15.31 88.27 0.90 51.95 119.25 142.43 0.60 3.34 2.20
SD or % 7.70 76 4.34 10.57 5.56 2074.27 144.06 3.86 0.38 0.50 25.40 11.76 8.11 1.00 11.66 24.04 69.78 0.10 2.98 1.35
p 0.667 0.081 0.159
<0.0001
<0.0001 0.237 0.374 0.506
<0.0001
<0.0001
<0.0001 0.776 0.079 0.191 0.825 0.299 0.641 0.0009 0.882 0.005 Control Group (n=96)
PHPT Group (n=75)
Table 2. The correlation between monocyte/HDL ratio and clini- cal, biochemical and hormonal parameters in the PHPT group.
Systolic blood pressure Diastolic blood pressure Calcium
Phosphorous Parathormone Vitamin D
Fasting Plasma Glucose LDL-cholesterol HDL-cholesterol BMI
CIMT CRP HOMA-IR
R2 0.276 0.127 0.201 0.061 0.082 0.063 -0.018 -0.135 -0.008 0.178 0.118 0.024 0.271
p 0.019 0.290 0.084 0.604 0.485 0.590 0.880 0.253 0.950 0.130 0.314 0.839 0.020 Abbreviations: BMI=body mass index; CIMT=carotid intima- media thickness; CRP=C-reactive protein; HOMA-IR=homeostasis model assessment of insulin resistance
MHR and cardiovascular risk factors in PHPT pati- ents. MHR was correlated with SBP and HOMA-IR;
however, it was not correlated with other cardio- metabolic risk factors including DBP, CRP, and CIMT.
We believe that ours is the first to evaluate the re- lationship between the MHR and cardiovascular risk factors in PHPT.
Monocytes migrate into tissue macrophages in inte- raction with platelets and endothelium, which exa- cerbates inflammation
4. The monocyte count was de- monstrated to predict the premature occurrence of coronary events, and the activation of monocytes is a key process in the beginning of atherosclerosis
16,17. HDL-C exhibits anti-inflammatory, antioxidant, and anti-platelet effects via several pathways, including contribution to the cholesterol outflow from mac- rophages, inhibition of endothelial adhesion prote- in expression, and encouraging reverse transport of oxidized molecules
18. HDL-cholesterol inhibits mo- nocyte activities and interrupts the transformation of monocytes to macrophages, which decreases inf- lammation
5. As a consequence, combining measure- ments of HDL-C and monocyte counts as the MHR might represent the basic inflammatory process.
The significance of MHR in CVD risk estimation has been evaluated in several diseases. Kanbay et al.
19first showed that increased MHR might predict CVD in chronic renal failure. Canpolat et al.
20reported that pre-ablation MHR was related with recurrence of atrial fibrillation following catheter ablation using cryoballoon. Pre-procedural MHR was demonstra- ted to be related to slow coronary flow and serio- us in-hospital adverse cardiac events and mortality following angiographic intervention in ST-segment elevation myocardial infarction (STEMI)
20,21. Cetin et al.
8found that MHR could predict stent throm- bosis following angiographic intervention for STE- MI. Bolayir et al.
22showed that an increased MHR independently predicted 30-day mortality in acute ischemic stroke. Cardiomyocytes, endothelial cells, and smooth muscle cells have PTH receptors
23, and increased PTH has been associated with myocardi- al fibrosis, calcification, and hypertrophy
24. Several
studies showed that PHPT had increased cardiovas- cular events and mortality, many of which improved after parathyroidectomy
9-13. Hypertension, hyper- lipidemia, CIMT, CRP, and insulin resistance are all well-studied CVD risk factors
25,26. Patients with PHPT have a higher risk for CVD and these patients have increased cardiovascular-related mortality
27. Various risk factors for CVD have been shown in patients with PHPT, including hypertension, and elevated CIMT, in- sulin resistance, and CRP
28-31. In the light of this infor- mation, we aimed to investigate whether MHR could be related to cardio-metabolic risk factors in patients with PHPT. Monocyte count, HDL-C levels and MHR did not differ between groups. We found a correla- tion between MHR and SBP and HOMA-IR; however, MHR was not correlated with other cardio-metabolic risk factors.
Hypertension (HT) leads to tissue damage in the heart and vessels, asymptomatic atherosclerosis and additional organ dysfunction
32. Aydin et al.
33demonstrated that MHR was associated with silent organ damage in HT. We observed that MHR and SBP were positively correlated, which might support the results of this study. Several studies showed that PHPT is associated with insulin resistance and incre- ased incidence of prediabetes and diabetes
34,35. We found a correlation between MHR and HOMA-IR, which might support these results.
The findings of our study might be explained by many of our patients possibly being in the early stage of the disease, which might explain why MHR does not represent an association with all cardio-metabolic risk factors. This constitutes a possible limitation of the study. As another limitation it was a single-center study with a small sample size.
In conclusion, the MHR did not increase in patients with PHPT. The MHR correlated with SBP and HOMA- IR; however, it was not associated with other cardio- metabolic risk factors including DBP, CIMT, and CRP.
Our findings do not support the thesis of MHR as a
potential marker of CVD in patients with PHPT. Ne-
vertheless, its association with SBP and HOMA-IR
might show the necessity for more comprehensive studies to enlighten this relation.
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